tbuckley/cabot-search huggingface dataset:
Mortality and the burden of subsequent malignant neoplasms in survivors of childhood cancer beyond age 50: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Rusha Bhandari, Yan Chen, Eric Jessen Chow, Rebecca M. Howell, Lisa Brazzamano Kenney, Kevin R. Krull, Wendy M. Leisenring, Paul C. Nathan, Joseph Philip Neglia, Kirsten K. Ness, Kevin C. Oeffinger, Claire Frances Snyder, Lucie Marie Turcotte, Florence Lennie Wong, Yutaka Yasui, Gregory T. Armstrong, Saro Armenian
Journal: Journal of Clinical Oncology (2023)

10052 Background: The first generation of survivors of childhood cancer is now older than 50 years (y) of age. There is a paucity of information on the risk for late mortality and the evolving burden of subsequent malignant neoplasms (SMNs) in these aging survivors. Methods: We assessed cause-specific mortality (National Death Index) and self-reported SMNs (excluding nonmelanoma skin cancers) among CCSS participants diagnosed between 1970-1999, conditional on having survived to 50y by 12/31/2017. There were 4,772 survivors alive at 50y eligible for mortality analyses. Of the 3,355 who completed a baseline CCSS questionnaire, 2,273 also completed a follow-up questionnaire at ≥50y and were included in the SMN analyses. Cumulative mortality, standardized mortality ratios (SMRs), and, for SMNs, cumulative burden, standardized incidence ratios (SIRs), and relative rate (RR) with 95% confidence intervals (CIs) were calculated, compared with the general US population and by survivor subgroups. Piecewise-exponential multivariable regression was used to identify risk factors associated with the development of SMNs after 50y. Results: Mean age at diagnosis was 14y (standard deviation 4.2y). Mortality: Among survivors who attained 50y of age, the subsequent 5y, 10y, and 15y incidences of all-cause mortality were 9%, 19%, and 35%, respectively, (overall SMR 3.7 [95% CI 3.4-4.1]). SMRs were highest for SMN (SMR 5.1 [95% CI 4.4-5.9]), pulmonary (SMR 4.7 [95% CI 3.3-6.5]) and cardiovascular (SMR 3.9 [95% CI 3.2-4.8]) causes of death. The highest SMR (SMR 9.2 [95% CI 7.7-10.8]) was seen in female survivors of Hodgkin lymphoma. SMN: By age 50y, 14% of CCSS participants reported &gt;1 SMN. History of SMN &lt;50y was independently associated with the rate of developing another SMN at &gt;50y (RR 1.6 [95% CI 1.1-2.3]). The most frequent SMNs ≥50y were breast (41%) in females and prostate (21%) in males, followed by gastrointestinal cancers in both (14% [females], 19% [males]). The cumulative burden of SMNs in survivors treated with radiation therapy (RT) increased sharply with age and exceeded 50 per 100 survivors by 65y (SIR 3.3 95%CI 2.0-5.2]). Survivors who did not receive RT had a SMN rate comparable to the general population (Table). Conclusions: This sentinel population of survivors of childhood cancer is at high risk for poor outcomes as they enter older adulthood. RT exposure and history of SMN &lt;50y are associated with increased risk for developing SMNs after 50y. The evolving burden of late morbidity attributed to SMNs may be lower for contemporary survivors projected to have less RT exposure. [Table: see text]
Bortezomib-induced cardiotoxicity: Real-world data from a single-center.
Authors: Suma Sri Chennapragada, Anil Ananthaneni, Shivani Sharma, Sindhu Priya Devarashetty, Runhua Shi, Poornima Ramadas
Journal: Journal of Clinical Oncology (2023)

e20008 Background: Bortezomib (Velcade) has emerged as the leading component of first-line therapies in both standard and high-risk multiple myeloma since the SWOGS0777 results were published in 2016. Although the incidence of cardiac side effects is reported to be lower with bortezomib compared to carfilzomib, standardized protocols for cardiac toxicity monitoring are unavailable. Currently, reported rates of cardiomyopathy with Velcade use range between 1-5%. We aim to examine bortezomib related cardiac adverse events and their association with demographics and traditional risk factors, especially in the setting of an ethnically diverse population that our hospital serves. Methods: Our institutional retrospective study extended between 01/2015 - 12/2020 and included patients aged &gt; 18 years who received Velcade for myeloma and excluded prisoners, pregnant women. Our primary objective was to investigate the incidence of Velcade-induced cardiomyopathy, arrythmias and coronary artery disease (CAD) as dependent variables. Independent variables included demographics, prior personal/family history of heart disease, comorbid conditions such as hypertension/diabetes/obesity/hyperlipidemia/smoking/atrial fibrillation/chronic kidney disease, myeloma subtype and RISS staging. Descriptive statistics were used to report frequencies and percentages. Fisher’s exact tests were used to report associations between dependent and independent variables. Results: This study included a total of 64 patients. Majority were males (58%), African Americans (79%), and had a mean age of 62 years. Free light chain and IgG kappa were the most common types of myeloma (73%). Mean dose of velcade and dexamethasone received was 52.4 mg/m2 and 834 mg respectively, over a mean duration of 26.14 weeks. Personal and family history of cardiovascular disease was reported in 39% and 23% patients respectively. A new diagnosis of cardiomyopathy was made in 14% of the patients. No new arrythmias or CAD were seen after Velcade use. In the unadjusted model, incidence of new cardiomyopathy was statistically significant in patients with personal (p = 0.043) and family history (p = 0.022) of cardiovascular disease. No other statistically significant associations were found with other independent variables, including dose or duration of velcade/steroid use. Multi-variate analysis is not reported due to low sample size. Conclusions: Our institution treats a diverse population with a higher multi-morbidity burden as opposed to physically and medically fit population recruited into clinical trials. This gives us an opportunity to bring forward some real world data. Given the higher incidence of cardiac toxicity in our study as opposed to current available data, we propose that high-risk patients with personal or family history of cardiovascular disease could benefit from closer monitoring during the course of their treatment with Velcade.
Implications for acute myeloid leukemia (AML) treatment and care during the COVID-19 pandemic: A Connect Myeloid Registry study.
Authors: Bart L. Scott, Mikkael A. Sekeres, Guillermo Garcia-Manero, David L. Grinblatt, Irene S. DeGutis, Pavel Kiselev, Ali McBride, Willem Heydendael, Edward Yu, Gail J. Roboz
Journal: Journal of Clinical Oncology (2023)

7021 Background: For patients (pts) with AML, timely treatment is critical. The COVID-19 pandemic broadly disrupted healthcare (eg, decreased blood donations), possibly causing delays in AML treatment and care. To determine the extent of the COVID-19 impact on AML, this analysis examines the effect of the pandemic on managing pts with AML in the Connect Myeloid Registry (NCT01688011). Methods: The Registry is a large, US, multicenter, prospective, observational cohort study that includes newly diagnosed pts with AML aged ≥55 y. Pt characteristics (including assessment for transplant) were analyzed from December 2013 to March 2020 (from Registry opening to the start of the pandemic; Period 1), from March 2020 to May 2021 (during major healthcare disruptions; Period 2), and from May 2021 to January 2022 (resource stabilization and increased vaccine availability; Period 3). Monthly COVID-19 incidence was calculated per weekly US government data (CDC COVID Data Tracker; 2023). Rates of visits (office, remote) and transfusions were calculated by monthly events/person-year. Overall survival (OS) was estimated using the Kaplan-Meier method. Results: In this analysis, 650 pts were included in Period 1, 87 pts in Period 2, and 36 pts in Period 3; demographics and baseline characteristics were balanced across periods. Prior to the COVID-19 pandemic (Period 1), 25.1% of pts were not assessed for transplant; however, after the onset of the pandemic, this increased (45.5% and 44.4% in Periods 2 and 3, respectively). When monthly US COVID-19 cases increased, in-person visits and transfusion rates generally decreased in the Registry (Table). The proportion of pts receiving oral-containing induction regimens was 49.4% (40/81) in Period 1 (starting in January 2019, due to FDA approval of venetoclax in November 2018) and 50.6% (44/87) in Period 2, with a slight increase to 63.9% (23/36) in Period 3. No significant differences in OS by period were observed. Conclusions: In this analysis of pts with AML in the real-world setting, a pattern of increased COVID-19 cases in the US was accompanied by fewer transfusions, fewer in-person visits, and fewer assessments for stem cell transplantation, without a significant impact on OS. Clinical trial information: NCT01688011 . [Table: see text]
Patient-derived MicroOrganoSpheres (MOS) and precision clinical decision-making for patients with multiple myeloma.
Authors: Rui Xi, Xiaobei Wang, Nicholas Baro, Renuka Raman, Shaun Steele, Elena Helman, Shengli Ding, Yubin Kang, Xiling Shen
Journal: Journal of Clinical Oncology (2023)

8047 Background: There are many multiple myeloma (MM) treatments and nearly all patients undergo continual cycles of treatment, response, and resistance. Selecting an effective therapeutic strategy is of critical importance; but there is currently a lack of patient-derived MM models that can enable functional precision medicine to help real-time clinical decision-making to guide individual patient treatment. Methods: We show a method to rapidly establish MM patient-derived MicroOrganoSheres (MOS), which are microscale, droplet-sized patient avatars that sustain the native tumor niche, including both stromal and immune compartments. We generated first-of-its-kind data showing that MM MOS predicted patient treatment outcomes and have the potential to guide clinical treatment decisions. We further developed high-throughput drug screen to demonstrate MM MOS response to FDA-approved single and combination therapies and developed MOS assays to predict patient responses to immunotherapies including bispecific and phagocytosis-inducing antibodies. Results: MM MOS established from patient bone marrow (BM) biopsies preserved CD138/CD38 tumor cells, stromal (e.g., osteoblast) cells, and all major immune cell populations (T, NK, B, macrophage, dendritic, and myeloid-derived suppressor cells) for 11 days in culture. We performed single and combo drug testing on MOS derived from 7 MM patients within 10 days of biopsy collection. Patients went on receiving treatments and their responses were assessed using International Myeloma Working Group response criteria. The MOS assay predicted responses of both treatment-naïve and refractory patient to standard-of-care regimens, including combinations of proteasome inhibitors (bortezomib, carfilzomib), immunomodulatory agents (lenalidomide) and DCEP. Moreover, the BM biopsy-derived MOS enabled high-throughput drug testing of single agents and combinations in 9-dose titrations, providing clinicians the ability to evaluate alternative treatment options. Furthermore, because MOS retain the immune compartments of the original tumor niche, we were able to evaluate patients’ response to bispecific T cell engagers and developed a phagocytosis assay to measure anti-tumor phagocytosis activity, which showed efficacy in both single-agent and combo settings. Multi-modal profiling and an AI image analysis pipeline provided robust measurements that confirmed the unique phenotypic profile of each patient sample, highlighting the critical unmet need to guide each patient to the optimal treatment. Conclusions: Based on this groundbreaking feasibility study, a subsequent clinical trial of 40 patients is current under IRB review to further validate the clinical power of MM MOS to predict patient outcome and to demonstrate utility as a viable functional precision medicine approach to inform treatment decisions in the clinic.
Bromodomain and extra-terminal (BET) inhibitor INCB057643 (LIMBER-103) in patients (pts) with relapsed or refractory myelofibrosis (R/R MF) and other advanced myeloid neoplasms: A phase 1 study.
Authors: Justin M. Watts, Anthony Hunter, Alessandra Iurlo, Blanca Xicoy, Francesca Palandri, Brandi Reeves, Alessandro M. Vannucchi, Prithviraj Bose, Rosa Ayala Diaz, Anna B. Halpern, Xuejun Chen, Francis Seguy, Feng Zhou, Fred Zheng, Pankit Vachhani
Journal: Journal of Clinical Oncology (2023)

7069 Background: BET proteins are epigenetic readers that regulate expression of critical oncoproteins involved in the pathophysiology of hematologic malignancies, including MF. INCB057643 is a small-molecule BET inhibitor evaluated as monotherapy and in combination with ruxolitinib (RUX) in pts with advanced malignancies in 2 previous phase 1/2 clinical trials. Methods: This ongoing phase 1, 3+3 dose-escalation/expansion study (NCT04279847) evaluates safety and tolerability of INCB057643 (4 mg once daily [qd]; escalation up to 12 mg qd) in pts aged ≥18 years as (1) monotherapy (part 1) in R/R MF, myelodysplastic syndromes (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndromes (MDS/MPN) or (2) added to RUX (part 2) in pts with MF and suboptimal response to RUX. The primary endpoint is safety and tolerability, including identification of dose-limiting toxicities (DLTs). Results: 13 pts have been treated in part 1 (4 mg, n=6; 8 mg, n=4; 10 mg, n=1; 12 mg, n=2), and 3 pts received 4 mg + RUX in part 2 (overall age range, 50–79 years; men, n=9; study treatment duration range, 15–314 days). 12 pts had MF, and 4 had MDS/MPN. All 6 pts in the 4-mg cohort discontinued treatment (3 for progressive disease [PD]; MF, n=2; MDS/MPN, n=1); 1 pt with MF in the 12-mg cohort discontinued for thrombocytopenia. The other 9 pts remain on treatment. Thrombocytopenia was the most common treatment-emergent adverse event (TEAE; n=9; Table) and the only TEAE leading to discontinuation (n=3). Grade ≥3 TEAEs occurring in ≥1 pt were thrombocytopenia (n=4), anemia (n=3), and hypokalemia (n=2). There were 8 serious AEs across 4 pts, with only COVID-19 occurring in &gt;1 pt (n=2); all but one (pneumonia) were considered unrelated to study treatment. There were 2 DLTs (thrombocytopenia [MDS/MPN pt] and hyperbilirubinemia [MF pt]; both 12-mg cohort) and 2 deaths (both 4-mg cohort due to PD [MF, n=1; MDS/MPN, n=1]). Conclusions: Treatment with INCB057643 monotherapy (4 and 8 mg qd) and in combination (4 mg qd) with RUX was generally well tolerated in this pt population. The 12-mg qd monotherapy dose was not tolerated and caused 2 DLTs. There were no treatment-related fatal events. Dose finding in part 1 is ongoing with 10 mg qd, after which a recommended phase 2 dose will be declared. Combination dose escalation is also ongoing. Preliminary efficacy including spleen size and symptoms will be available for presentation. Clinical trial information: NCT04279847 . [Table: see text]
Expression of CD47 and CALR in myeloproliferative neoplasms: Potential new therapeutical targets.
Authors: Ciro Roberto Rinaldi, Kristian Boasman, Matthew Simmonds
Journal: Journal of Clinical Oncology (2023)

e19079 Background: Myeloproliferative neoplasms (MPN) are myeloid malignancies characterized by overproduction of mature blood cells, hyperplastic bone marrow and tendency to evolve into acute myeloid leukaemia. In solid tumours, calreticulin (CALR) overexpression produces a pro-phagocytic signal and is counteracted by concomitant expression of anti-phagocytic CD47, reflecting an apoptosis vs survival mechanism. Increases of both CALR and CD47 on the cell membrane have been observed in response to chemotherapy, however their role in myeloid malignancies is poorly understood. We Investigate the expression and cellular localisation of CALR and CD47 in untreated and treated patients with essential thrombocythemia (ET), polycythemia vera (PV) myelofibrosis (MF), in comparison with healthy controls. Methods: Mononuclear cells were collected by Ficoll separation, from peripheral blood of 30 MPN (8 PV, 16 ET, 6 MF); 18 MPN patients received cyto-reductive therapies (Hydroxyurea, Anagrelide or Ruxolitinib); and 4 controls. Cells were fractionised into 4 compartments: membrane, cytoplasm, cytosol and nucleus. Proteins were extracted using TRIzol, with CALR and CD47 protein expression analysed by western blotting. Results: Total CALR and CD47 protein expression increased in MPN samples compared with controls (CALR- 7.9 vs 5.1; CD47- 2.7 vs 2.2 fold, respectively). CD47 showed higher expression of its overall protein on MPN cell membranes when compared with CALR (22% vs 13.9%). We observed a significant reduction of CALR expression in all MPN subtypes when patients were treated with cyto-reductive agents (ET- untreated 43.3% vs treated 2%, PV- 3.6% vs 2.2%, ET- 21% vs 11%). Interestingly we have observed a significant increase in CD47 cell membrane expression after treatment in MF and PV (CD47 in MF- untreated 11.8% vs treated 34.3%, PV-11.4% vs 35.9%), suggesting an anti-phagocytic effect induced by cytotoxic drugs. In ET cell membranes however, CD47 expression is reduced after cyto-reductive treatment (22% vs 16.6%), suggesting instead a prophagocytic effect. Conclusions: CD47, but not CALR, is overexpressed on the membrane of patients with MPN, suggesting a role for CD47 as a strong antiphagocytic signal responsible for immune survival in MPN. We observed a significant difference in CD47 expression across different MPN subtypes with a significant increase in CD47 expression in PV and MF but not ET. The use of anti-CD47 antibodies could represent a new strategy to enhance the treatment response in particular in PV and MF.
Demographic predictors of successful transition to adult survivorship care for survivors of pediatric cancer.
Authors: Renee Gilbert, Carolyn Bates, Kyla Alsman, Joy M. Fulbright, Becky N. Lowry, Eve-Lynn Nelson
Journal: Journal of Clinical Oncology (2023)

10050 Background: There is a growing number of childhood cancer survivors in the U.S. (Chow et al., 2020) who are at risk for experiencing negative long-term health outcomes (Oeffinger et al., 2006). Current guidelines state the importance of receiving risk-based follow-up at adult survivorship clinics, yet available estimates suggest that less than 50% of survivors receive yearly survivorship care (Landier et al., 2004; Daly et al., 2018). The transition from pediatric to adult care is a difficult process, with various factors acting as barriers (Devine et al., 2017). The present study sought to evaluate demographic predictors of successful transition to adult survivorship care in a Midwestern clinic serving a large urban and rural catchment area. Methods: The study includes adult survivors of childhood cancer (n = 203) who received pediatric or adult survivorship care in a Midwestern metropolitan area from 2015 to 2022. For this study, successful transition to adult care was defined as attending at least one appointment in the adult survivorship clinic. Dates of clinic attendance, cancer diagnosis, insurance data, and zip code were abstracted from the medical record. 86.2% of survivors had commercial insurance, 13.8% had government -sponsored insurance, self-pay or other insurance. Participant zip codes were 66.7% urban, 19.5% metropolitan (low and high commuting), 9.2% micropolitan, and 4.6% rural. Survivor ages ranged from 20 to 68 years (M = 29.48, SD = 7.74) and 53.2% were female. Participant-reported race/ethnicity was 90.1% White, 5.4% Hispanic, 3.4% Black and 1% Other. Results: 66% of the sample attended at least 1 appointment in the adult survivorship clinic. Chi-square analyses revealed a significant relationship between insurance type and attendance at the clinic, [Χ2(1) = 16.60, p &lt; .001], such that a greater proportion of survivors with commercial insurance transitioned to adult survivorship care (71%), compared to government-assisted (Medicare), self-pay or other insurance (32%). Analyses revealed a significant relationship between rurality and transition, [Χ2(3) = 14.11, p &lt; .01], such that a greater proportion of survivors from urban areas transitioned (74%) compared to rural areas (22%). Race/ethnicity, gender and cancer type were not significantly associated with transition. Conclusions: Results suggest that a lack of commercial insurance and rurality served as risk factors for not successfully transitioning to an adult survivorship clinic, highlighting opportunities for improvement in clinic reach.
A phase II study of palbociclib combined with retifanlimab in patients with advanced dedifferentiated liposarcoma.
Authors: Sandra P. D'Angelo, Evan Rosenbaum, Rodrigo Gularte Mérida, Mark Andrew Dickson, Mary Louise Keohan, Mrinal M. Gounder, Ping Chi, Sujana Movva, Ciara Marie Kelly, Viswatej Avutu, Jason Earl Chan, Jae Cho, Matthew Biniakewitz, Grace Cho, Joseph Patrick Erinjeri, Robert A Lefkowitz, Cristina R. Antonescu, Li-Xuan Qin, Samuel Singer, William D. Tap
Journal: Journal of Clinical Oncology (2023)

TPS11590 Background: Dedifferentiated liposarcoma (DDLPS) is characterized by near universal amplification of the cyclin-dependent kinase 4 ( CDK4) gene. Palbociclib (P) is a selective CDK4/6 inhibitor that has demonstrated promise in phase II studies of DDLPS. Anti-PD-1 therapy has also shown signals of efficacy, with an approximate overall response rate of 10% in DDLPS patients. CDK4/6 inhibitors upregulate antigen processing and presentation, suppress regulatory T cells, and increase inflammation within the tumor microenvironment. Combined with anti-PD-1 blockade, they can induce an inflamed T cell phenotype and tumor regression in pre-clinical models. We hypothesize that P combined with the anti-PD-1 inhibitor retifanlimab (R) will be safe and tolerable and have synergistic activity leading to activation of T cells and resultant clinical responses. Methods: NCT04438824 is a phase II study of P plus R with a safety lead-in phase. Patients with unresectable or metastatic DDLPS who have received any number of prior therapies are eligible to enroll. On the safety lead-in phase, 6 patients received P (125 mg once daily orally for 21 days followed by 7 days off) plus R (500 mg IV flat dose), repeated in 28-day cycles. P was initiated as monotherapy two weeks prior to initiation of R. The primary endpoint of the safety lead-in was to confirm the recommended phase two dose of the combination. Accrual to the safety lead-in has been completed and a pre-planned phase II expansion portion was opened to accrual. A study amendment was passed that revised the treatment schedule on the expansion cohort to start both P and R concomitantly on day 1 of each cycle. This revised schedule was based on recent data demonstrating the superior safety of a concurrent, rather than staggered, dosing schedule. The primary endpoint of the expansion phase is to estimate the best overall response rate (ORR) by RECIST 1.1. Secondary endpoints include describing the safety and estimating clinical benefit rate, duration of response, progression-free, and overall survival. A total of 30 patients treated with the revised dosing scheme will be enrolled onto the expansion phase. Twelve patients have been enrolled to date. An ORR of 5% will be considered not promising, while an ORR of 25% will be considered promising. The null hypothesis will be rejected if 4 or more patients have a confirmed objective response to treatment. This design has a type I error rate of 0.06 and a type II error rate of 0.04. Mandatory pre- and on-treatment biopsies will be performed for correlative analyses. Clinical trial information: NCT04438824 .